Left to right: Dr Surendra Singh, Colm Duffy, Prof Pat Guiry and Dr Tasadaque Ali-Shah
Our bodies’ basic defense against injury is inflammation. Inflammation, however, has its dark side: unchecked, it can cause damage to the tissue. Cystic fibrosis is one of the many diseases now linked to an overactive inflammatory response. Others include asthma, rheumatoid arthritis and gum disease. Phagocytosis, where neutrophils are enveloped and digested by other cells, is a key event in the control of inflammation.
Regulating or halting the acute inflammatory response is a complex process involving “stop” signals. Biological molecules called lipoxins were first isolated in the 1980s.
Some of the beneficial action ascribed to aspirin is now believed to be due to the formation of lipoxins. A multi-disciplinary team including Professor Pat Guiry of the Centre for Synthesis and Chemical Biology and Professor Catherine Godson, Professor of Medicine and Therapeutics at UCD Conway Institute are unravelling the story of inflammation and the role played by lipoxins in regulating the process.
“Lipoxins have been shown to promote phagocytosis of the neutrophils,” says Professor Guiry, Professor of Organic Chemistry at the UCD School of Chemistry and Chemical Biology. “However the therapeutic potential of lipoxins is limited by reactions with enzymes in our bodies which break them down.”
In the search for new therapies for diseases, researchers often look to nature for inspiration. The challenge for synthetic organic chemists is to create molecules which are superior to those found in the body. Professor Guiry’s research group have synthesised novel lipoxin-based molecules that help shed light on inflammation and offer a new approach to halting its damaging effects.
Professor Guiry believed that an analogue could be synthesised with the potency of the lipoxins, but with an improved “shelf-life” or chemical stability. Biological testing of the lipoxin analogues has given promising results. “The Lipoxin A4 analogue shows a significant increase of phagocytosis, comparable with the naturally occurring lipoxin, while the Lipoxin B4 analogue also stimulates phagocytosis,” says Professor Guiry.
Further modification may increase the potency of the analogues by blocking other metabolic pathways. “Work is underway on the synthesis of other analogues and their subsequent biological evaluation,” he concludes. “Several chronic inflammatory conditions may be amenable to therapeutic intervention by stable synthetic lipoxin analogues.”
